DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. The laboratory work has now been completed on many of the conditions selected for copy number variant testing. Copy number variants have been identified in several conditions of interest. We have completed our investigation of heterotaxy-associated copy number variants; written up the results; and they have been published in Genetics in Medicine. Our analysis of copy number variants in posterior urethral valves has been completed and submitted for publication. The analysis for Klippel Trenaunay Weber snydrome has been completed and a manuscript is in preparation. The analysis for prune belly syndrome has been completed and a manuscript will be prepared. The analysis for Ebstein's anomaly will be completed shortly and a manuscript will be prepared. We have also collaborated with large groups doing genome wide association studies. Our work on idiopathic hypertrophic pyloric stenosis (IHPS) is noteworthy. IHPS is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. We previously collaborated with investigators in Denmark and Sweden to conduct a genome-wide search for candidate genes. We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. These findings have been published in JAMA.We are expanding our work on pyloric stenosis to include other genes. We have initiated new collaboration with the CDC's National Birth Defects Prevention Study. In conjunction with Dr. Paul Romitti at the University of Iowa, we will be searching for genetic factors associated with choanal atresia, a defect in which the nasal passages fail to develop normally. This study involves testing samples from New York State and from the collaborative group that formed the National Birth Defects Prevention Study. IRB clearances have now been obtained and samples selected. Copy number variant testing will begin shortly. We will be collaborating with another consortium following up on our work described in last year's report on craniosynostosis (see Justice et al. Nature Genetics). The previous work focused on saggital craniosynostosis. The future work will expand on this to look for genetic factors associated with defects in other sutures. This work has received external funding and is ongoing. We have established a collaboration with the Statens Serum Institut in Copenhagen, Denmark to examine genetic factors in congenital hydrocephalus. We have identified samples for confirmatory testing of SNPs from their GWAS study.